There has been significant interest in developing devices which permit the non-invasive monitoring of constituents in the blood and tissues of the body. Some success has been achieved in designing devices which measure the oxygen content in the blood. The devices are known as oxymeters.
Oxymeters determine the level of oxygen in the blood by measuring the amount of light absorbed in the tissue. In operation, a probe beam is generated having a wavelength in the 400 to 600 nanometer range. The probe beam is directed through the tissue into the blood stream. The portion of the blood stream carrying oxygen (oxyhemoglobin) has a high level of absorption in this wavelength range. Non-oxygenated hemoglobin and other human tissue are much more transmissive at these wavelengths. Accordingly, by measuring the level of absorption which occurs when the probe beam light passes through the tissue, the level of oxygen in the blood can be determined.
This approach for the non-invasive analysis of oxygen content in the blood has been relatively successful due to a few factors. First, there is a considerable amount of blood present in the human body (ten percent) and the red blood cells, which contain the hemoglobin, account for forty-five percent of the total volume of the blood. In addition, and as noted above, certain light wavelengths exist which are highly absorbed in oxygenated blood and which have much lower absorption levels in the other constituents of the body.
Attempts to use optical absorption schemes to analyze other constituents in the body have been much less successful because the conditions are less favorable. For example, many other constituents of interest are present in much lower concentrations in the body. Moreover, even though the constituents of interest will have certain specific absorption bands, these absorption bands are typically shared with other constituents in the body. Therefore, isolation and measurement of particular constituents by optical absorption has not been possible.
One constituent in the body for which there is great interest in developing non-invasive monitoring techniques is glucose, since monitoring glucose levels can significantly aid in the treatment of diabetes. It is now well established that a principal method of preventing some of the more serious effects of diabetes is to regularly monitor the glucose level in the blood stream and then maintain that level within a normal range. At the present time, the most common method for monitoring glucose levels requires obtaining a small blood sample. The blood sample is then subjected to a chemical reaction wherein the glucose is oxidized to form gluconic acid, hydrogen peroxide and a hydronium ion. This reaction can be monitored using dry chemical strips either spectrophotometrically or electrochemically.
The use of the glucose strip method has become quite common. Unfortunately, this approach is painful, messy, complex, expensive and prone to error. In addition, since the skin must be pierced and blood drawn, issues regarding the spread of life threatening infections arise.
Efforts are underway to provide alternatives to the blood-glucose strip method. At the present time, attempts are being made to monitor glucose levels in saliva, sweat, subcutaneous tissue and the eye. However, glucose concentrations, particularly in the saliva and sweat, lag in time behind the actual concentrations in the blood and therefore do not give an accurate picture of current glucose levels in the blood.
To avoid these problems, efforts have been made to measure blood glucose in a non-invasive manner using optical techniques similar to those used in measuring oxygen levels in the blood. One method relies upon shining near infrared light through a finger or earlobe. Unfortunately, while the glucose molecule absorbs in this wavelength region, other, more highly concentrated constituents in the body (such as water and proteins) absorb in this wavelength region as well. Thus, the absorption caused by glucose is minimal compared to the total absorption of other constituents.
Even with this minimal absorption, some positive results can be achieved by applying various forms of statistical analyses to the measurements. More specifically, by collecting data and comparing it to a calibration model, some initial success has been achieved. However, to date, various factors which tend to reduce the accuracy of the results have not been fully resolved. These factors include tissue temperature, endogenous metabolites, hemoglobin concentration, repeatability of the placement of the tested region (finger, earlobe) in the testing device and subject to subject variability.
Another technique for the non-invasive monitoring of glucose is based on the optical activity of the molecule. Glucose, like many other carbohydrates and monosaccharides is optically active. When polarized light is passed through a mixture including an optically active constituent, the axis of polarization of the light will be rotated by an amount proportional to the concentration of the optically active constituent. For typical glucose levels in the blood (approximately 100 mg/dL), the optical rotation of light will be only 5 to 9 millidegrees per centimeter path length.
Prior art polarimeters are capable of measuring optical rotation at this low level. However, the various elements of the body, including tissue, blood etc. scatter, absorb and depolarize light, such that the polarization rotation induced by the glucose will be masked. To minimize these problems, efforts have been made to monitor the optical activity of glucose by measuring the effect in the eye where scattering and absorption is minimized.
These latter efforts have provided some promising results. However, problems with scattering and absorption still exist. Moreover, the eye exhibits birefringence which also interferes with the measurement. Finally, it is unknown how comfortable patients will be shining lights into their eyes to measure glucose levels.
Accordingly, there is still a strong need to develop an accurate, non-invasive technique for monitoring glucose levels in the blood.
The invention described herein addresses this need through the use of a thermal wave excitation and detection system. The concept and approaches for evaluating samples using a thermal wave type analysis are well established today. Commercial thermal wave detection systems are employed primarily in the semiconductor fabrication field where the devices are used to monitor ion implant dosage, defects and other features. Examples of such systems can be found in the following U.S. Pat. Nos. 4,521,118; 4,522,510; 4,636,088; 4,579,463; 4,634,290 and 4,632,561.
In general, thermal wave detection systems include a means for creating a periodic heating in the sample. In the case of the equipment discussed above, the preferred heat source is an intensity modulated laser beam which can be tightly focused to the micron range important for semiconductor analysis. The periodic heat source functions to generate periodic thermal waves which propagate outwardly interacting with various features in the sample. These thermal waves will function to periodically vary a number of different physical and optical parameters of the sample such as reflectivity, transmission, absorption, scattering and local deformation of the sample surface.
The variations of these different parameters can be monitored using a number of different techniques. In the systems discussed above, the optical parameters are investigated using a probe beam of radiation which is also focused onto the sample. Periodic changes in the probe beam, such as reflected power, transmitted power or scattering, are monitored using a phase synchronous detection system. These periodic changes can provide valuable information about the surface and subsurface characteristics of the sample.
In the past, thermal wave techniques also have been used experimentally to analyze biological samples. These experiments have been primarily limited to photoacoustic spectroscopy experiments wherein the sample is heated with a modulated optical beam and the periodic absorption of this probe beam as a function of wavelength is measured. For a more complete discussion, see Photoacoustics and Photacoustic Spectroscopy, Allan Rosenscwaig, Wiley Interscience, 1980.
The prior investigations of both semiconductors and biological material relate to samples where it is relatively straightforward to target the constituent of interest. For example, when investigating ion dopant levels in semiconductors, the sample is treated as a uniform absorber of the pump beam and probe beams. The output signal is a function of a fairly homogeneous local region of the sample. In contrast, and as noted above, the blood stream can include a number of different constituents which inhibits the analysis of specific constituents of interest.
Accordingly, it is an object of the subject invention to provide an improved thermal wave generation and detection system which is particularly suited for investigating characteristics of non-homogeneous samples.
It is a further object of the subject invention to provide a system which can preferentially analyze selected constituents of a non-homogeneous sample.
It is another object of the subject invention to provide a system for analyzing particular constituents in the blood stream of a mammal.
It is still a further object of the subject invention to provide a system for the non-invasive monitoring of the glucose levels in the blood stream of a mammal.
It is still another object of the subject invention to provide a thermal wave detection system which provides spatial discrimination permitting analysis of selected constituents in a non-homogeneous sample